Is there a dose-response relationship between exposure to indoor allergens and symptoms of asthma?

Abstract

Over the last 40 years most populations in the western world have retreated indoors, and we now spend 95% or more of our time in tightly sealed, overheated buildings. During this same period, the morbidity and prevalence of asthma have progressively increased, and multiple reports on the association between asthma and sensitization to the common indoor allergens have been published. Indeed, there are many reasons for considering that there must be a causal relationship between exposure to indoor allergens and asthma.1Sporik RB Chapman MD Platts-Mills TAE House dust mite exposure as a cause of asthma [Editorial].Clin Exp Allergy. 1992; 22: 897-906Crossref PubMed Scopus (260) Google Scholar On the other hand, several groups have failed to find a clear dose-response relationship between symptoms of asthma and current exposure to indoor allergens.2Platts-Mills TAE Thomas WR Aalberse RC Vervloet D Chapman MD Co-Chairmen Dust mite allergens and asthma: report of a 2nd international workshop.J ALLERGY CLIN IMMUNOL. 1992; 89: 1046-1060Abstract Full Text PDF PubMed Scopus (581) Google Scholar, 3Call RS Smith TF Morris E Chapman MD Platts-Mills TAE Risk factors for asthma in inner city children.J Pediatr. 1992; 121: 862-866Abstract Full Text PDF PubMed Scopus (365) Google Scholar, 4Sporik R Ingram JM Price W Sussman JH Honsinger RW Platt-Mills TAE Association of asthma with serum IgE and skin-test reactivity to allergens among children living at high altitude: tickling the dragon's breath.Am J Respir Crit Care Med. 1995; 151: 1388-1392Crossref PubMed Scopus (222) Google Scholar, 5Sporik R Holgate ST Platts-Mills TAE Cogswell J Exposure to house dust mite allergen (Der p I) and the development of asthma in childhood: a prospective study.N Engl J Med. 1990; 323: 502-507Crossref PubMed Scopus (1473) Google Scholar In this issue of the JOURNAL, Marks et al. (pages 441-8) of Sydney, Australia report that the concentration of mite allergens was no higher in the houses of asthmatic patients with mite allergy than in other houses in the town. Ingram et al. have also recently reported that among schoolchildren who are allergic to cat or dog allergens, there is very little relationship between current exposure and whether the children report symptoms of asthma (see pages 449-56). These findings are important both because the results confirm those of previous studies and because they appear to question whether there is a causal relationship between indoor allergen exposure and asthma. In 1873 Charles Blackley published his studies on catarrhus aestivus, which included a detailed description of the technique for counting pollen grains and an estimate of the weight of pollen necessary to produce symptoms.6Blackley CH Experimental research in the causes and nature of Catarrhus aestivus (hay fever or hay asthma). (Reprinted from Bailliere Tindall & Cox, 1873). Dawson Publishing Co, London1959Google Scholar The fact that patients only experienced symptoms at that time of year when pollen was in the air was a major argument for a causal relationship between pollen exposure and hay fever. More recently, studies on the daily symptom scores of groups of patients with hay fever, followed up through the season, have shown a good dose-response relationship with the pollen count.7Norman PS Lichtenstein LM Ishizaka K Diagnostic tests in ragweed hay fever. A comparison of direct skin tests, IgE antibody measurements, and basophil histamine release.J ALLERGY CLIN IMMUNOL. 1973; 52: 210-224Abstract Full Text PDF PubMed Scopus (178) Google Scholar In a few areas where the pollen counts are very high it is also possible to observe a seasonal peak in asthma attacks.8Reid MJ Moss RB Hsu YP Kwasnicki JM Commerford TM Nelson BL Seasonal asthma in northern California: allergic causes and efficacy of immunotherapy.J ALLERGY CLIN IMMUNOL. 1986; 78: 590-600Abstract Full Text PDF PubMed Scopus (168) Google Scholar, 9Pollart SM Reid MJ Fling JA Chapman MD Platts-Mills TAE Epidemiology of emergency room asthma in northern California: association with IgE antibody to rye grass pollen.J ALLERGY CLIN IMMUNOL. 1988; 82: 224-230Abstract Full Text PDF PubMed Scopus (84) Google Scholar, 10Creticos PS Reed CE Norman PS et al.The NIAID cooperative study of the role of immunotherapy in ragweed-induced adult asthma: 3rd year clinical endpoints; cost effectiveness [Abstract].J ALLERGY CLIN IMMUNOL. 1993; 91: 227Google Scholar Similarly, an increased severity of asthma among Alternaria-sensitive individuals has been reported during the "Alternaria season."11O'Hollaren MT Yunginger J Offord KP et al.Exposure to an aeroallergen as a possible precipitating factor in respiratory arrest in young patients with asthma.N Engl J Med. 1991; 324: 359-363Crossref PubMed Scopus (598) Google Scholar The essence of these reports is that there is a simple technique for identifying and counting the specific airborne particle (e.g., pollen grain or Alternaria spore), which provides a reliable "index of exposure." It is also central to these observations that outdoor particles change with the season from near zero to greater than 200 particles per cubic meter. The most obvious difference between indoor and outdoor allergens is that the airborne particles indoors cannot be identified or counted microscopically. Thus there is no indoor equivalent of the pollen count. Although counting mites, cockroaches, or cats may be a reasonable guide to the quantity of allergen in a house, the best measurement of exposure established to date is the immunochemical assay of major allergens in extracts of dust obtained from bedding, carpets, or sofas.2Platts-Mills TAE Thomas WR Aalberse RC Vervloet D Chapman MD Co-Chairmen Dust mite allergens and asthma: report of a 2nd international workshop.J ALLERGY CLIN IMMUNOL. 1992; 89: 1046-1060Abstract Full Text PDF PubMed Scopus (581) Google Scholar, 12Platts-Mills TAE Chapman MD Dust mites: immunology, allergic disease, and environmental control [Review].J ALLERGY CLIN IMMUNOL. 1987; 80: 755-775Abstract Full Text PDF PubMed Scopus (435) Google Scholar, 13Luczynska CM Arruda LK Platts-Mills TAE Miller JD Lopez M Chapman MD A two-site monoclonal antibody ELISA for the quantitation of the major Dermatophagoides spp. allergens, Der p I and Der f I.J Immunol Methods. 1989; 118: 227-235Crossref PubMed Scopus (393) Google Scholar The concentration of allergens in houses can vary widely either in different parts of a house or within a town.14Platts-Mills TAE Hayden ML Chapman MD Wilkins SR Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma.J ALLERGY CLIN IMMUNOL. 1987; 79: 781-791Abstract Full Text PDF PubMed Scopus (258) Google Scholar Because of this, it was assumed that measurements of allergen would have to be made in each patient's house. For many indoor allergens (e.g., cat, dog, cockroach), there is little or no seasonal variation, and even in areas where there are large seasonal fluctuations in humidity (e.g., Cincinnati, Ohio and Charlottesville, Virginia), the seasonal variations in mite allergen levels are not as great as those for outdoor allergens.14Platts-Mills TAE Hayden ML Chapman MD Wilkins SR Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma.J ALLERGY CLIN IMMUNOL. 1987; 79: 781-791Abstract Full Text PDF PubMed Scopus (258) Google Scholar, 15Arlian LG Bernstein IL Gallagher JS The prevalence of house dust mites, Dermatophagoides spp, and associated environmental conditions in homes in Ohio.J ALLERGY CLIN IMMUNOL. 1982; 69: 527-532Abstract Full Text PDF PubMed Scopus (175) Google Scholar The case for a causal relationship would best be supported by evidence for a dose-response relationship between allergen exposure and symptoms. Most of the data have been published in relation to specific threshold values for sensitization or symptoms. In 1969 Voorhorst et al.16Voorhorst R Spieksma FThM Varekamp N House dust mite atopy and the house dust mite Dermatophagoides pteronyssinus (Troussart, 1897). Stafleu's Scientific Publishing Co, Leiden1969Google Scholar suggested that the presence of 100 or more mites per gram of dust created a risk of allergic symptoms and asthma. Subsequently, when assays for the Group I allergens (Der p I and Der f I) became available, a threshold level of 2 μg/gm dust was proposed.2Platts-Mills TAE Thomas WR Aalberse RC Vervloet D Chapman MD Co-Chairmen Dust mite allergens and asthma: report of a 2nd international workshop.J ALLERGY CLIN IMMUNOL. 1992; 89: 1046-1060Abstract Full Text PDF PubMed Scopus (581) Google Scholar, 14Platts-Mills TAE Hayden ML Chapman MD Wilkins SR Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma.J ALLERGY CLIN IMMUNOL. 1987; 79: 781-791Abstract Full Text PDF PubMed Scopus (258) Google Scholar, 17Platts-Mills TAE de Weck AL Chairmen Dust mite allergens and asthma—a world wide problem.J ALLERGY CLIN IMMUNOL. 1989; 83: 416-427Abstract Full Text PDF PubMed Scopus (562) Google Scholar (This level is broadly equivalent to 100 mites per gram.) Initially, it was not clear whether this was a threshold for production of IgE antibodies or for symptoms; however, over the last 10 years this distinction has become clear. Studies from England, Australia, France, Denmark, the United States, and Germany have all demonstrated that children growing up in houses with greater than 2 μg of Group I mite allergen per gram of dust are at risk for developing positive skin test responses and serum IgE antibodies.18Peat JK Britton WJ Salome CM Woolcock AJ Bronchial hyperresponsiveness in two populations of Australian schoolchildren. III. Effect of exposure to environmental allergens.Clin Allergy. 1987; 17: 297-300Google Scholar, 19Korsgaard J Mite asthma and residency. A case-control study on the impact of exposure to house-dust mites in dwellings.Am Rev Respir Dis. 1983; 128: 231-235PubMed Google Scholar, 20Lau S Falkenhorst G Weber A et al.High mite-allergen exposure increases the risk of sensitization in atopic children and young adults.J ALLERGY CLIN IMMUNOL. 1989; 84: 718-725Abstract Full Text PDF PubMed Scopus (334) Google Scholar Much of the data applies to genetically atopic individuals. In the July 1994 issue of the JOURNAL, Kuehr et al.21Kuehr J Frischer T Meinert R et al.Mite exposure is a risk for the incidence of specific sensitization.J ALLERGY CLIN IMMUNOL. 1994; 94: 44-52Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar of Frieburg, Germany published an elegant prospective study of 1802 children showing a dose-response relationship between the concentration of mite allergen on bedding and sensitization of "atopic" school-age children. In that study, increased sensitization became significant at ~2 μg of Group I allergen per gram. In contrast, their data showed that sensitization of children who did not have a preexisting positive skin test response to an inhalant allergen other than mite (i.e., were not atopic) required exposure to concentrations of mite allergen as high as 80 μg/gm.21Kuehr J Frischer T Meinert R et al.Mite exposure is a risk for the incidence of specific sensitization.J ALLERGY CLIN IMMUNOL. 1994; 94: 44-52Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar Many studies on the relationship between indoor allergen exposure and symptoms of asthma assume that patients with the highest concentrations of allergen in their houses should have the worst symptoms. Indeed, it is often implied that this would be expected from a comparison with hay fever. This view is based on an oversimplification of pollen allergy. In a cross-sectional population study during the ragweed pollen season, only sensitization to ragweed would be useful in predicting which individuals would have symptoms. However, in a population in which all individuals were exposed to pollen, even accurate measurements of IgE antibody to ragweed or quantitative skin tests would not accurately predict severity of symptoms. Among a group selected only by the presence of positive skin test responses to ragweed (or grass) pollen, there will be individuals who do not experience symptoms of hay fever during the relevant pollen season. Similarly, there are individuals with positive skin test results for mite or cat who can nonetheless live in a house with high levels of mite or cat allergen with minimal or no symptoms of asthma, atopic dermatitis, or rhinitis.2Platts-Mills TAE Thomas WR Aalberse RC Vervloet D Chapman MD Co-Chairmen Dust mite allergens and asthma: report of a 2nd international workshop.J ALLERGY CLIN IMMUNOL. 1992; 89: 1046-1060Abstract Full Text PDF PubMed Scopus (581) Google Scholar, 3Call RS Smith TF Morris E Chapman MD Platts-Mills TAE Risk factors for asthma in inner city children.J Pediatr. 1992; 121: 862-866Abstract Full Text PDF PubMed Scopus (365) Google Scholar, 5Sporik R Holgate ST Platts-Mills TAE Cogswell J Exposure to house dust mite allergen (Der p I) and the development of asthma in childhood: a prospective study.N Engl J Med. 1990; 323: 502-507Crossref PubMed Scopus (1473) Google Scholar, 22Gelber LE Seltzer LH Bouzoukis JK Pollart SM Chapman MD Platts-Mills TAE Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital.Am Rev Respir Dis. 1993; 147: 573-578Crossref PubMed Scopus (472) Google Scholar We have attempted to illustrate our concept of this relationship in Fig. 1. The conclusion is that even if there were a simple dose-response relationship between quantitative exposure to indoor allergens and the symptoms of asthma for each individual, the variability within a group of patients would obscure it. Three different kinds of studies have been used to examine the relationship between exposure to indoor allergens and symptoms of asthma among allergic individuals: (1) comparison between different geographic areas, (2) comparison of houses within a community, and (3) "avoidance experiments." Studies comparing different geographic areas are often confounded by the low prevalence of sensitization in areas with low exposure. Thus in Alice Springs, Australia or Los Alamos, New Mexico there are very few "natives" who are allergic to mites. Thus it is difficult to study the symptoms of allergic but unexposed individuals.4Sporik R Ingram JM Price W Sussman JH Honsinger RW Platt-Mills TAE Association of asthma with serum IgE and skin-test reactivity to allergens among children living at high altitude: tickling the dragon's breath.Am J Respir Crit Care Med. 1995; 151: 1388-1392Crossref PubMed Scopus (222) Google Scholar, 7Norman PS Lichtenstein LM Ishizaka K Diagnostic tests in ragweed hay fever. A comparison of direct skin tests, IgE antibody measurements, and basophil histamine release.J ALLERGY CLIN IMMUNOL. 1973; 52: 210-224Abstract Full Text PDF PubMed Scopus (178) Google Scholar, 23Peat JK Tovey E Mellis CM Leeder SR Woolcock AJ Importance of house dust mite and Alternaria allergens in childhood asthma: an epidemiological study in two climatic regions of Australia.Clin Exp Allergy. 1993; 23: 812-820Crossref PubMed Scopus (247) Google Scholar In cross-sectional studies within communities, such as those by Tovey et al. and Ingram et al. in this issue, the results have not been consistent. Most studies that compare the houses of asthmatic patients with those of nonasthmatic, nonallergic control subjects in the same town do not demonstrate significant differences in the concentrations of allergen. In Atlanta, the concentrations of mite and cockroach allergens were very similar in dust from the apartments of asthmatic children and control subjects.3Call RS Smith TF Morris E Chapman MD Platts-Mills TAE Risk factors for asthma in inner city children.J Pediatr. 1992; 121: 862-866Abstract Full Text PDF PubMed Scopus (365) Google Scholar Among adult patients who came to an emergency department in Wilmington, Delaware, the strong correlation between sensitization and asthma was only slightly strengthened by factoring in current exposure to relevant allergens.22Gelber LE Seltzer LH Bouzoukis JK Pollart SM Chapman MD Platts-Mills TAE Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital.Am Rev Respir Dis. 1993; 147: 573-578Crossref PubMed Scopus (472) Google Scholar On the other hand, in Aarhus, Denmark, Korsgaard19Korsgaard J Mite asthma and residency. A case-control study on the impact of exposure to house-dust mites in dwellings.Am Rev Respir Dis. 1983; 128: 231-235PubMed Google Scholar reported that asthmatic patients with mite allergy lived in houses with higher levels of allergen than random control subjects. In Marseilles, Vervloet et al.24Vervloet D Charpin D Haddi E et al.Medication requirements and house dust mite exposure in mite-sensitive asthmatics.Allergy. 1991; 46: 554-558Crossref PubMed Scopus (56) Google Scholar observed a dose-response relationship between mite allergen concentration in dust and the severity of asthma symptoms among individuals with mite allergy. Avoidance studies strongly suggest that continuing exposure plays a role in most cases of chronic asthma. Major reductions (i.e., ≥95%) in allergen exposure can reduce symptoms, bronchial reactivity, and signs of inflammation.25Charpin D Birnbaum J Haddi E et al.Altitude and allergy to house dust mites: a paradigm of the influence of environmental exposure on allergic sensitization.Am Rev Respir Dis. 1991; 143: 983-986Crossref PubMed Google Scholar, 26Platts-Mills TAE Tovey ER Mitchell EB Moszoro H Nock P Wilkins SR Reduction of bronchial hyperreactivity during prolonged allergen avoidance.Lancet. 1982; 2: 675-678Abstract PubMed Scopus (575) Google Scholar, 27Kerrebijn KF Endogenous factors in childhood CNSLD: methodological aspects in population studies.in: Bronchitis III. Royal Vangorcum Assen, The Netherlands1970: 38-48Google Scholar, 28Boner AL Niero E Antolini I Valletta EA Gaburro D Pulmonary function and bronchial hyperreactivity in asthmatic children with house dust mite allergy during prolonged stay in the Italian Alps (Misurina 1756m).Ann Allergy. 1985; 54: 42-45PubMed Google Scholar This is strong evidence that continuing exposure plays an important role in symptoms. However, reductions in bronchial hyperreactivity (BHR) during allergen avoidance commonly take weeks or months and are not observed in all the patients (Fig. 1). Several assumptions are inherent in the expectation of a simple relationship between allergen concentrations and symptoms of asthma. The first assumption is that the measurement of allergens in dust samples is an accurate index of exposure. The second assumption is that the size of skin test reaction or concentration of IgE antibody is a good guide to the inflammatory response that occurs in the lungs when allergen particles land on the epithelium. The third assumption is that the severity of symptoms is closely related to the degree of inflammation in the lungs. The truth is that there are significant problems in each case. It is obvious that measuring the concentration of cat, dog, mite, or cockroach allergen in dust obtained from a carpet is not a direct measurement of the allergen entering the lungs. However, there is no method of measuring allergen entering the lungs, and despite one enthusiastic report, most groups have not been able to obtain measurements of airborne allergens, which could be used to evaluate exposure in epidemiologic studies.29Price JA Pollock J Little SA Longbottom JL Warner JO Measurements of airborne mite allergen in houses of asthmatic children.Lancet. 1990; 336: 895-897Abstract Full Text PDF PubMed Scopus (130) Google Scholar, 30Swanson MA Agarwal MK Reed CE An immunochemical approach to indoor aeroallergen quantitation with a new volumetric air sampler: studies with mite, roach, cat, mouse and guinea-pig antigens.J ALLERGY CLIN IMMUNOL. 1987; 76: 724-729Abstract Full Text PDF Scopus (147) Google Scholar, 31Luczynska CM Li Y Chapman MD Platts-Mills TAE Airborne concentrations and particle size distribution of allergen derived from domestic cats (Felis domesticus): measurements using cascade impactor, liquid impinger and a two site monoclonal antibody assay for Fel d I.Am Rev Respir Dis. 1990; 141: 361-367Crossref PubMed Google Scholar, 32De Blay F Kassel O Chapman MD Ott M Verot A Pauli G Mise en evidence des allergenes majeurs des blattes par test ELISA dans la poussiere domestique.La Press Med. 1992; 21: 1685-1694PubMed Google Scholar Furthermore, because allergen is airborne on particles, which range in size from 2 to 20 μm in diameter, knowing the quantity airborne may not be an adequate measurement of lung exposure without knowledge of the particle size.31Luczynska CM Li Y Chapman MD Platts-Mills TAE Airborne concentrations and particle size distribution of allergen derived from domestic cats (Felis domesticus): measurements using cascade impactor, liquid impinger and a two site monoclonal antibody assay for Fel d I.Am Rev Respir Dis. 1990; 141: 361-367Crossref PubMed Google Scholar, 33Tovey ER Chapman MD Wells CW Platts-Mills TAE The distribution of dust mite allergen in the houses of patients with asthma.Am Rev Respir Dis. 1981; 124: 630-635PubMed Google Scholar Certainly, the results of natural exposure cannot be compared with a challenge in which the same quantity of allergen is delivered through a nebulizer. Although measurements of reservoir dust may be rather distant from an actual measurement of allergen entering the lungs, nonetheless, for mite and cockroach allergens are the best index of exposure that is available. For cat allergen it is clear that airborne allergen is carried on a wide range of particle sizes and that the relationship between airborne levels and floor samples is extremely variable.34Luczynska CM Li Y Chapman MD Platts-Mills TAE Airborne concentrations and particle size distribution of allergen derived from domestic cats (Felis domesticus): measurements using cascade impactor, liquid impinger and a two site monoclonal antibody assay for Fel d 1.Am Rev Respir Dis. 1990; 141: 361-367Crossref PubMed Scopus (302) Google Scholar Swanson et al.35Swanson MC Campbell AR Klauck MJ Reed CE Correlations between levels of mite and cat allergens in settled and airborne dust.J ALLERGY CLIN IMMUNOL. 1989; 83: 776-783Abstract Full Text PDF PubMed Scopus (107) Google Scholar reported a poor correlation between airborne Fel d 1 and floor dust allergen. More recently, Bollinger et al.36Bollinger ME Eggleston PA Flanagan E Wood RA Cat antigen in homes with and without cats may induce allergic symptoms.J ALLERGY CLIN IMMUNOL. 1995; (in press)Google Scholar have shown that significant amounts of Fel d 1 could be found airborne in houses without a cat, even though the levels in the floor dust were generally less than 1 μg of Fel d 1 per gram of dust. This is important because several recent studies have confirmed that measurable cat allergen is common in houses without a cat.4Sporik R Ingram JM Price W Sussman JH Honsinger RW Platt-Mills TAE Association of asthma with serum IgE and skin-test reactivity to allergens among children living at high altitude: tickling the dragon's breath.Am J Respir Crit Care Med. 1995; 151: 1388-1392Crossref PubMed Scopus (222) Google Scholar, 22Gelber LE Seltzer LH Bouzoukis JK Pollart SM Chapman MD Platts-Mills TAE Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital.Am Rev Respir Dis. 1993; 147: 573-578Crossref PubMed Scopus (472) Google Scholar Calculations of the concentration of allergen in a pollen grain or a mite fecal particle suggest that the local concentration of allergen where they land in the lungs may be very high (i.e., >1 mg/ml).33Tovey ER Chapman MD Wells CW Platts-Mills TAE The distribution of dust mite allergen in the houses of patients with asthma.Am Rev Respir Dis. 1981; 124: 630-635PubMed Google Scholar This concentration would be expected to produce a local patch of "inflammation," including local eosinophil recruitment and a T-cell response. There is overwhelming evidence from bronchial provocation experiments that this response occurs selectively in allergic individuals; however, there is very little evidence to show that it is quantitatively related to the size of skin test reaction or titer of IgE antibody. Presumably, multiple foci or repeated stimulation may have cumulative effects on the lungs, and the speed with which these foci heal may represent another major variable. There are good reasons for believing that the consequences of an inflammatory response can last for weeks or months, which would further obscure a simple dose-response relationship.26Platts-Mills TAE Tovey ER Mitchell EB Moszoro H Nock P Wilkins SR Reduction of bronchial hyperreactivity during prolonged allergen avoidance.Lancet. 1982; 2: 675-678Abstract PubMed Scopus (575) Google Scholar, 27Kerrebijn KF Endogenous factors in childhood CNSLD: methodological aspects in population studies.in: Bronchitis III. Royal Vangorcum Assen, The Netherlands1970: 38-48Google Scholar, 28Boner AL Niero E Antolini I Valletta EA Gaburro D Pulmonary function and bronchial hyperreactivity in asthmatic children with house dust mite allergy during prolonged stay in the Italian Alps (Misurina 1756m).Ann Allergy. 1985; 54: 42-45PubMed Google Scholar, 37Cockcroft DW Ruffin RE Dolovich J Hargreave FE Allergen-induced increase in non-allergic bronchial reactivity.Clin Allergy. 1977; 7: 503-513Crossref PubMed Scopus (683) Google Scholar, 38Cockcroft DW Mechanism of perennial allergic asthma.Lancet. 1983; 2: 253-256Abstract PubMed Scopus (146) Google Scholar If the timing of first exposure to allergens is critical to the development of the immune response and/or bronchial inflammation, this would also make it more difficult to demonstrate a relationship between current exposure and symptoms of asthma. In our prospective study in England we reported that asthma symptoms at age 11 correlated better with the allergen concentration that had been found in the subjects' houses at age 2 than with the current concentration (i.e., at age 11).5Sporik R Holgate ST Platts-Mills TAE Cogswell J Exposure to house dust mite allergen (Der p I) and the development of asthma in childhood: a prospective study.N Engl J Med. 1990; 323: 502-507Crossref PubMed Scopus (1473) Google Scholar We still do not understand the difference between the response to allergen in an asthmatic patient and that in a patient with rhinitis. When segmental provocation of the lungs is performed, the response, as judged by the number of inflammatory cells in bronchoalveolar lavage, is similar. Thus the relationship of "inflammation," BHR, and symptoms is not well understood. However, Cockcroft et al.37Cockcroft DW Ruffin RE Dolovich J Hargreave FE Allergen-induced increase in non-allergic bronchial reactivity.Clin Allergy. 1977; 7: 503-513Crossref PubMed Scopus (683) Google Scholar have demonstrated a highly significant relationship between late reactions after bronchial provocation and prolonged increases in BHR. Recently, Boner et al.39Boner AL Peroni D Sette L Valletta EA Piacentini G Effects of allergen exposure-avoidance on inflammation in asthmatic children.Allergy. 1993; 48: 119-124Crossref PubMed Scopus (21) Google Scholar have shown that reductions in number of eosinophils in lung secretions from asthmatic children correlated with decreases in BHR during allergen avoidance at Misurina in the Italian Alps.40Carswell F The relationship between mite allergen exposure and asthma severity.Clin Exp Allergy. 1995; 25: 99-101Crossref PubMed Scopus (10) Google Scholar, 41Lemansky RF Dick EG Swenson CA Busse WW Rhinovirus upper respiratory infection increases airway reactivity in late asthmatic reactions.J Clin Invest. 1989; 83: 1Crossref PubMed Scopus (352) Google Scholar Those experiments provide more evidence suggesting that the inflammation is a cause of the BHR and that continued allergen exposure is necessary to maintain inflammation. The traditional textbook view of allergens as triggers of acute attacks of asthma leads to the assumption that acute episodes would be related to short-term increases in allergen exposure. As is clear from the preceding discussion, we now see allergens as an important long-term cause of inflammation. Short-term increases in symptoms can be triggered by many different irritants including cold air, exercise, passive smoke, ozone, and changes in the weather. All of these will confound any relationship between current allergen exposure and the severity of symptoms.37Cockcroft DW Ruffin RE Dolovich J Hargreave FE Allergen-induced increase in non-allergic bronchial reactivity.Clin Allergy. 1977; 7: 503-513Crossref PubMed Scopus (683) Google Scholar However, none of these factors has been convincingly shown to be a cause of respiratory tract "inflammation." In contrast, recent studies in several different laboratories have provided clear evidence that intercurrent viral infection can exacerbate symptoms and increase eosinophil or eosinophil products (major basic protein and eosinophil cationic protein) in the respiratory tract.41Lemansky RF Dick EG Swenson CA Busse WW Rhinovirus upper respiratory infection increases airway reactivity in late asthmatic reactions.J Clin Invest. 1989; 83: 1Crossref PubMed Scopus (352) Google Scholar, 42Pattemore PK Johnston SL Bardin PG Viruses as precipitants of asthma symptoms. I. Epidemiology.Clin Exp Allergy. 1992; 22: 325-336Crossref PubMed Scopus (289) Google Scholar, 43Duff AL Pomeranz ES Gelber LE et al.Risk factors for acute wheezing in infants and children: viruses, passive smoke, and IgE antibodies to inhalant allergens.Pediatrics. 1993; 92: 535-540PubMed Google Scholar This is important because it appears that there is a positive interaction between rhinovirus (or picornavirus) infection and the response to allergen exposure.41Lemansky RF Dick EG Swenson CA Busse WW Rhinovirus upper respiratory infection increases airway reactivity in late asthmatic reactions.J Clin Invest. 1989; 83: 1Crossref PubMed Scopus (352) Google Scholar If correct, this means that many, or even most, exacerbations of symptoms in allergic children are not triggered by a short-term change in allergen exposure. It is generally assumed that the dose-response relationship between allergen exposure and asthma symptoms is linear. However, it is likely that the relationship is complex and for each individual it could be linear, log linear, or sigmoidal. If the response curves were sigmoidal, this could have important consequences. In many areas, all houses would have allergen concentrations above the level that is sufficient to maintain bronchial reactivity. Thus a difference between 5 μg/gm and 20 μg/gm might not be significant in causing symptoms. Certainly, in the suburbs of Sydney, Australia, where mite levels are generally high, all the houses could have sufficient allergen to maintain bronchial reactivity in a large proportion of patients with asthma (see Marks et al., pages 441-8). A sigmoidal relationship could also have great relevance to studies of avoidance treatment. A reduction in allergen exposure from 20 μg/gm to 5 μg/gm might not be sufficient to produce a measurable clinical effect in a group of patients.44Marks GB Tovey ER Green W Shearer M Salome CM Woolcock AJ The effect of changes in house dust mite allergen exposure on the severity of asthma.Clin Exp Allergy. 1995; 25: 114-118Crossref PubMed Scopus (60) Google Scholar An equally important concept is that the dose response for symptoms may not be comparable to the dose response for sensitization. In addition, patients who require very little exposure for sensitization to develop are not necessarily those who only require low levels